Pegylated Liposomal Doxorubicin vs. Topotecan for Recurrent Epithelial Ovarian Cancer
Abstract & Commentary
To compare the efficacy and safety of pegylated liposomal doxorubicin (PLD) and topotecan in patients with recurrent epithelial ovarian cancer that recurred after or didn’t respond to first-line platinum-based chemotherapy, Gordon and colleagues conducted a study in which patients with measurable and assessable disease were randomized to receive either PLD 50 mg/m2 as a 1-hour infusion every 4 weeks or topotecan 1.5 mg/m2/d for 5 consecutive days every 3 weeks. Patients were stratified prospectively for platinum sensitivity and for the presence or absence of bulky disease. A total of 474 patients were treated (239 PLD and 235 topotecan). They comprised the intent-to-treat population. The overall progression-free survival rates were similar between the 2 arms (P = .095). The overall response rates for PLD and topotecan were 19.7% and 17.0%, respectively (P = .390). Median overall survival times were 60 weeks for PLD and 56.7 weeks for topotecan. Data analyzed in platinum-sensitive patients demonstrated a statistically significant benefit from PLD for progression-free survival (P = .037), with medians of 28.9 for PLD vs. 23.3 weeks for topotecan. For overall survival, PLD was significantly superior to topotecan (P = .008), with a median of 108 weeks vs. 71.1 weeks. The platinum-refractory subgroup demonstrated a nonstatistically significant survival trend in favor of topotecan (P = .455). Severe hematologic toxicity was more common with topotecan and was more likely to be associated with dosage modification, or growth factor or blood product use. Gordon et al concluded that the comparable efficacy, favorable safety profile, and convenient dosing support the role of PLD as a valuable treatment option in this patient population. (Gordon A, et al. J Clin Oncol. 2001;19:3312-3322).
Comment by David M. Gershenson, MD
Once patients with epithelial ovarian cancer relapse, their curability approaches zero. However, the good news is that we have an increasing number of active agents against recurrent ovarian cancer. These include the 2 drugs compared in this study—PLD and topotecan—and other chemotherapeutic drugs, such as gem-citabine, vinorelbine, hexamethylmelamine, oral etoposide, irinotecan, paclitaxel, and docetaxel. In addition, hormonal agents such as tamoxifen have an objective response rate of approximately 15%. Of course, there are several new "targeted therapies" in clinical trials and on the horizon. These include the anti-angiogenesis agents, the epidermal growth factor receptor agents, monoclonal antibodies, tyrosine kinase inhibitors, and vaccines. Currently, PLD and topotecan are among the most popular agents for treatment of platinum-resistant (cancer that progresses on or recurs within 6 months of completing primary chemotherapy) recurrent ovarian cancer. The present study found no differences between the 2 drugs in objective response rates, progression-free survival, or overall survival. However, in the platinum-sensitive subgroup, there was an apparent difference in progression-free survival and overall survival favoring PLD. In addition, the toxicity profile tended to favor PLD, with much less severe adverse event reporting. Unfortunately, Gordon et al used the standard dose of topotecan in this study—a dose that several experts believe is too high considering its associated severe myelotoxicity. Although Gordon et al do not emphasize the finding, the response rates in the platinum-resistant subgroups were generally lower than previously reported in other studies—12.3% for PLD and 6.5% for topotecan; these response rates are quite disappointing in such a large cohort. Otherwise, there were not many surprises in this large, randomized trial.
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